IL-6 is a cytokine which is also called B cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-lymphatic cells (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokine that influences various functions of cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 has been reported to induce the. maturation of T-lymphatic cells (Lotz et al., J. Exp. Immunol. 18: 1253-1258, 1988).
IL-6 transmits its biological activity through two types of proteins on the cell. One of them is IL-6 receptor, a ligand-biding protein with a molecular weight of about 80 kD, to which IL-6 binds. IL-6 receptor occurs not only in a membrane-bound form that penetrates through and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region.
The other protein is a membrane-bound protein gp130 having a molecular weight of about 130 kD that is involved in signal transduction. IL-6 and IL-6 receptor form the IL-6/IL-6 receptor complex which, after binding to gp130, transmits its biological activity to the cell (Taga, T. et al., J. Exp. Med. (1987) 166, 967).
IL-6 antagonist is a substance that inhibits the transduction of biological activity of IL-6. As the IL-6 antagonist, there have been known so far antibody directed against IL-6 (anti-IL-6 antibody), antibody directed against IL-6 receptor (anti-IL-6 receptor antibody), and antibody directed against gp130 (anti-gp130 antibody). In addition, there are also known IL-6 antagonists that are disclosed in the International Patent Application WO 95-00852, the International Patent Application WO 95-11303, the International Patent Application WO 96-34104, the International Patent Application WO 96-18648, the International Patent Application WO 96-17869, Japanese Unexamined Patent Publication (Kokai). No. 7(1995)-324097, and Japanese Unexamined Patent Publication (Kokai) No. 8(1996)-311098.
Anti-IL-6 receptor antibody has been described in several reports (Novick D. et. al., Hybridoma (1991) 10, 137-146, Huang, Y. W. et al., Hybridoma (1993) 12, 621-630, International Patent Application WO 95-09873, French Patent Application FR 2694767, U.S. Pat. No. 521,628). A humanized PM-1 antibody was obtained by grafting the complementarity determining regions (CDRs) of a mouse antibody PM-1 (Hirata et al., J. Immunology (1989) 143, 2900-2906), to a human antibody (the International Patent Application WO 92-19759).
On the other hand, in many autoimmune diseases and allergic diseases, there are T cells that recognize specific antigens (sensitized T cells) and these sensitized T cells are known to be involved in the pathology of such diseases. For example, there are known the presence of sensitized T cells that are directed to myelin basic protein in multiple sclerosis (Zhang, J. et al., J. Exp. Med (1994) 179, 973-984), S antigen in uveitis (Nussenblatt, R. B. et al., Am. J. Ophthalmol (1980) 89, 173-179), thyroglobulin in chronic thyroiditis, foods and acarids for atopic dermatitis (Kubota, Y. et al., J. Dermatol (1993) 20, 85-87, Kondo, N. et al., J. Allergy Clin. Immunol (1993) 91, 658-668), bacteria, viruses, fungi, etc. in delayed hypersensitivity, and metal, Japanese lacquer, etc. in contact dermatitis, and the like.
Furthermore, it is also possible to induce pathological states similar to those in humans by immunizing an animal with these antigens or by introducing antigen-specific sensitized T cells into a non-immunized animal. Based on these facts, it is thought that sensitized T cells play an important role in the above diseases. Currently, steroids and/or immunosuppressive agents are used for the treatment of these diseases, but they are symptomatic treatments and require administration for a long period of time, which eventually poses the problem of side effects.
It has not been known so far that IL-6 antagonists as described above exhibit a suppressive effect on sensitized T cells and a therapeutic effect on the diseases in which sensitized T cells are involved.